tbuckley/cabot-search huggingface dataset:
PATH-24. A CASE SERIES OF LONGER THAN EXPECTED SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Jerica Lomax, Xiao-Tang Kong, Daniela Bota
Journal: Neuro-Oncology (2023)

Abstract Despite interventions with surgery, radiation, and chemotherapy, Glioblastoma (GBM) remains a difficult cancer to treat. Only 6.9% of patients survive five years post-diagnosis1 and the median overall survival is reported to be in the range of 14-15 months.2Glioblastoma patients who harbor an IDH-mutation have a known improved survival rate over their IDH-wildtype counterparts and under the recent WHO 2021 Classification of CNS tumors, IDH-mutational status is now an established criteria for the classification of high-grade gliomas. MGMT methylation status is also a well-described prognostic factor in GBM. MGMT methylated patients have a more favorable prognosis and better response to conventional treatment with temozolomide.3 It is rare but there are some IDH-wildtype, MGMT-unmethylated GBM patients who survive longer than 4 years. Therefore, it is important to identify other potential favorable factors for longer survival in the unfavorable cohort of patients with IDH-wildtype and MGMT-unmethylated GBM. Case Series: Eighty-five GBM patients who had next generation sequencing completed at the University of California, Irvine were reviewed. Of 85 patients, 4 patients (4.7%) were IDH-wildtype, MGMT-unmethylated and lived longer than 4 years. We evaluated the pathology, clinical characteristics, treatment course, and molecular findings of these 4 long term GBM survivors with IDH-wildtype and MGMT-unmethylated status. Discussion: This case series of 4 cases of patients with IDH-wildtype, MGMT-unmethylated GBM with longer than expected survival did not reveal a ubiquitously prevalent molecular marker for long term survival based on review of next-generation sequencing results. 2 out of the 4 patients harbored an uncommon MTAP copy number loss mutation, which may warrant further investigation into the significance of this mutation on prognosis. 3 out of 4 patients received a vaccine-based intervention through clinical trial which may support ongoing investigation into the additional benefit this specific population of GBM patients may have from vaccine-based therapy.
IMMU-10. VISUALIZING GBM SUCCESS: SOC + TRIPLE-ARMED IMMUNOTHERAPY CASE REPORT--<i>FUTURE TRIAL DESIGN OPTIONS</i>
Authors: Daniel Arbess, Sean Khozin
Journal: Neuro-Oncology (2023)

Abstract Pro-neural GBM IV patient's family-guided, provider-consulted N-of-1 journey from SOC through development and implementation of a triple-armed personalized immunotherapy combination. No tumor progression observed 4-years post-diagnosis, 3-years post-anti-tumor therapy. Therapeutic combination included SOC + (a) checkpoint inhibition, (b) patient tumor-specific-antigen peptide vaccine, (c) TME metabolic reprogramming; and (d) bioavailable supplements. Presentation will highlight inductive observations relevant to potential trial design and future practice, including (among others): Relative Benefits of Vaccine Technologies (lysate, TSA) &amp; delivery vectors (DC, sub-q, mRNA); Suggested Order of Immunotherapy Components (TME metabolic, vaccine, CPI); Monitoring: Imaging Interpretational Challenges (distinguishing immune-inflammation from tumor progression); Ongoing Immunogenicity Analysis; Patient Wellbeing: Managing Treatment Effects (epitope spread/inflammatory overshoot); and Implications for Neuro-Immunotherapy Trial Design: Combining/comparing/optimizing elements of SOC, TME metabolic reprogramming, Vax &amp; CPI.
STEM-23. TARGETING SOX2 IN GLIOBLASTOMA CELLS REVEALS HETEROGENEITY IN SOX2 DEPENDENCY
Authors: Erika Dalmo, Gabriela Rosén, Mia Niklasson, Tobias Bergström, Hrvoje Miletic, Cecilia Lindskog, Karin Forsberg-Nilsson, Sven Nelander, Lene Uhrbom, Fredrik Swartling, Bengt Westermark
Journal: Neuro-Oncology (2023)

Abstract The malignant primary brain tumor glioblastoma (GBM) has a dismal prognosis and current treatment options are insufficient to cure patients. The stem cell transcription factor SOX2 has been indicated as vital for GBM stem cell maintenance in vitro and GBM tumor formation in vivo, rendering it a putative therapeutic target for GBM. However, a few studies, including previous work from our lab, suggest a dichotomy in SOX2 dependence between different patients. To elucidate whether SOX2 independent GBMs exist and if so, how they are distinguished, we have investigated how altered SOX2 expression affects a panel of primary human GBM lines cultured under stem cell conditions. We found that elevated SOX2 expression inhibited proliferation in a dose-dependent manner in three out of four GBM cell lines. Global gene expression analysis showed that cells representing proliferation-inhibited and refractory cell lines end up on different ends of the developmental- to injury response GBM stem cell axis, were resistance to SOX2 overexpression was connected to an injury response expression profile. CRISPR/Cas9 mediated SOX2 knockout revealed a SOX2 independence in the refractory cell line, where cells lacking SOX2 could be propagated both in vitro and in vivo, implicating SOX2 as a non-essential gene for injury response-driven GBM stem cells. In current work, SOX2-dependent cell lines are engineered to express inducible exogenous SOX2 with concomitant endogenous SOX2 knockout, providing a system where SOX2 can be turned off at any time point. This system will be used in further studies elucidating the nature of SOX2 dependence and independence in GBM stem cells.
TMIC-62. COMPLEMENT FACTOR H IS A NOVEL LIGAND FOR THE INDUCIBLE T CELL CO-STIMULATOR AND PROMOTES SURVIVAL OF REGULATORY T CELLS IN THE GLIOMA MICROENVIRONMENT
Authors: Karolina Smolag, Jakub Olszowka, Rebecca Rosberg, Elinn Johansson, Elisabet Marinko, Karin Leandersson, David O′Connell, Valeria Governa, Emre Can Tüysüz, Mattias Belting, Martin Myriam, Alexander Pietras, Anna Blom
Journal: Neuro-Oncology (2023)

Abstract The survival rates of glioma patients have not shown significant improvement in recent years despite aggressive treatment and advancements in immunotherapy. This lack of response to treatment can be attributed in part to the immunosuppressive microenvironment commonly found in gliomas, where regulatory T cells (Tregs) play a critical role in immunologic tolerance. In this study, we aimed to investigate the influence of complement factor H (FH) on Tregs within the glioma microenvironment. Our findings revealed that FH acts as a novel ligand for the inducible T cell costimulator (ICOS). This interaction between FH and ICOS promotes the survival of Tregs. Furthermore, FH enhances the functional capabilities of Tregs that are crucial for modulating the tumor microenvironment. These include the secretion of transforming growth factor beta and interleukin 10, as well as the suppression of effector T cell proliferation. Immunostaining of human and mouse gliomas demonstrated that cancer cells directly produce FH. Additionally, database analysis revealed an association between upregulated FH expression, the presence of Tregs, and poor prognosis in glioma patients. We validated these findings in a glioma mouse model, where knockdown of FH expression showed a clear tendency to prolong survival. Given that the accumulation of Tregs is indicative of a poor prognosis and represents a promising target for therapy, it is crucial to consider FH expression when evaluating the effectiveness of immunotherapies against glioma.
QOL-15. THE PIVOTAL TRIDENT STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Wenyin Shi, Martin Glas, David Roberge, Lawrence Kleinberg, Suriya Jeyapalan, Samuel Goldlust, Seema Nagpal, Leonardo Lustgarten, Stephanie Combs, Ryo Nishikawa, David Reardon, Rachel Grossman
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: TTFields are electric fields which act to disrupt processes necessary for cancer cell division and tumor progression. TTFields therapy is a noninvasive, locoregional treatment with US FDA approval for ndGBM and recurrent GBM, as well as pleural mesothelioma. TTFields therapy concomitant with maintenance TMZ is standard of care in ndGBM after chemoradiation based on the pivotal EF-14 study (NCT00916409) reporting significant improvements in progression-free survival (PFS) and overall survival (OS) vs TMZ alone. Preclinical and pilot clinical studies subsequently demonstrated that concomitant TTFields therapy also enhanced the therapeutic effect of radiotherapy (RT). TRIAL DESIGN: TRIDENT (EF-32, NCT04471844) is a pivotal multicenter study investigating TTFields therapy (200 kHz) concomitant with RT/TMZ in adult patients with histologically confirmed ndGBM. Eligibility criteria include life expectancy (≥ 3 months) and Karnofsky performance status (≥ 70). Patients (n≈950) stratified by MGMT promoter methylation status and extent of resection are randomly assigned 1:1 to receive TTFields therapy from the first day of chemoradiation (experimental arm), or approximately 4 weeks after completion of chemoradiation (control arm). All patients will receive TTFields therapy uninterrupted for 24 months, or until second disease progression (PFS2). The primary endpoint is median OS and other endpoints include survival rates at 1 and 2 years, PFS (overall, PFS2, and rates at 6 and 12 months), overall radiological response, safety, quality of life and dependence of OS on TTFields dose. The sample size is powered for a hazard ratio of &amp;lt; 0.8 (5% type I error). A stratified log-rank test will be used to test the hypothesis that OS is significantly improved with first line TTFields therapy/RT/TMZ vs RT/TMZ. This global study is open at sites in 11 countries.
NIMG-68. TEMPORAL CHANGES IN TUMOR COMPOSITION DIFFER ACROSS TUMOR GRADE IN GLIOMA
Authors: Savannah Duenweg, Samuel Bobholz, Allison Lowman, Margaret Stebbins, Aleksandra Winiarz, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract Gliomas are the most common primary adult brain tumor in the United States and their biological heterogeneity makes it difficult to assess and treat tumor progression over time. This study used conventional MRI tumor segmentations to determine longitudinal growth differences between low grade (≤ G2), G3, and G4 gliomas. A total of 60 patients with at least three scans collected before death were organized into low-grade (n = 9), G3 (n = 13), and G4 (n = 38) gliomas at initial diagnosis. T1, T1C, FLAIR, and T2 images from every timepoint across all patients were used as input for tumor segmentation, using BraTS, to segment contrast enhancement (CE), FLAIR hyperintensity (FH), and the necrotic core (NC). Volumes within each segmentation and the time between each subsequent MRI was calculated, where the first post-surgical MRI was considered time 0. Linear mixed models were fitted for each segmentation volume, where Time, Group (i.e., G2-4) and their interaction (Group*Time) were fixed effects and subject was a random effect. We found that Time and Group*Time interaction were significant predictors of FH growth (p &amp;lt; 0.001 and 0.04, respectively); however, no group-level differences were observed in FH volumes over time. Group was the only significant predictor of CE growth (p = 0.006). Specifically, G4 growth was greater than G2 and had a trending increase than G3 (p = 0.003 and 0.08, respectively). Group, Time, and Group*Time were all significant predictors of NC growth (p = 0.04, 0.001, and 0.01, respectively). G4 NC growth was significantly greater than both G2 and G3 (both p &amp;lt; 0.05). No difference any of these tumor segmentations growth between G2 and G3 was detected. These results further show the heterogeneity in glioma growth over time and the necessity to assess how treatment effects longitudinal tumor composition progression and overall survival.
INNV-26. THE CHALLENGE OF TREATING ADULTS WITH MEDULLOBLASTOMA – THE CANON EXPERIENCE
Authors: Julie Bennett, Mary-Jane Lim-Fat, Katrina Roberto, Natalie Massey, Vijay Ramaswamy, Arjun Sahgal, Warren Mason, Erin Morgan, Sarah Ironside, Osama Ahmed, Derek Tsang, Sunit Das, Uri Tabori, Cynthia Hawkins, Seth Climans
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Medulloblastoma (MB) is the most common malignant brain tumor in children, but relatively rare in adults. Pediatric treatment paradigms may be applied to young adults despite a paucity of data in this population. Here we aim to describe the characteristics of adults with MB presented at the Canadian Adolescent and Young Adult Neuro-Oncology Network (CANON) multi-disciplinary national rounds along with provider’s current practices in treating these patients. METHODS Cases presented at national rounds between April 2021 – June 2023 including young adults with MB were analyzed to describe patient characteristics and themes of the questions posed. In addition, a survey was sent to all Canadian neuro-oncologists asking about current practice patterns and we describe responses. RESULTS A total of 15 young adults with MB were discussed in this time frame. There were 13 males and 2 females with a median age of 30 years (range 20-61). Subgrouping was available on 12/15, with 7 (46.7%) SHH-activated, 3 (20%) WNT-activated and 3 (20%) Group 4 MB. Ten of the patients presented were new diagnoses with discussion regarding treatment including dose of radiation and chemotherapy protocol. In addition, 4/10 had an incomplete resection and there was discussion regarding a second look surgery. Three patients were presented at time of recurrence, with 2/3 being extra-cranial recurrence. There were a total of 25 responses to the Canadian survey on medulloblastoma, showing variation in practice. Most patients got craniospinal irradiation with 36 Gy. There was wide variation in terms of chemotherapy regimens offered. CONCLUSION There are differences in treatment practices for adults with MB across Canada with many questions regarding what treatment should be offered, specifically related to chemotherapy regimen. This highlights the desperate need to harmonize practice and examine adults as a unique cohort.
RADT-43. LONG TERM OUTCOMES OF PEDIATRIC AND ADULT CENTRAL NEUROCYTOMA—THE ROLE OF SALVAGE RADIOTHERAPY AND CONSERVATIVE MANAGEMENT
Authors: Yufan Yang, Nitin Wadhwani, Shuhua Zheng, James Chandler, Maciej Lesniak, Matthew Tate, Adam Sonabend, John Kalapurakal, Craig Horbinski, Rimas Lukas, Roger Stupp, Priya Kumthekar, Sean Sachdev
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CN, but the optimal treatment paradigm following subtotal resection (STR) and or scarcer pediatric cases has yet to be established—including the role of radiation therapy (RT). Herein, we reviewed the long-term outcomes of CN patients at our institution. METHODS Patients between the years 2001 and 2021 with a pathologic diagnosis of CN were reviewed. Demographic, treatment, and tumor characteristics (histopathological and molecular) were recorded. Recurrence free survival (RFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Post-RT tumor volumetric regression analysis was performed. RESULTS Seventeen adults (≥ 18 years old) and 5 children (&amp;lt; 18 years old) met the criteria for data analysis (n = 22). With a median follow-up of 6.9 years (range: 1.2-42.8 years), there was zero tumor-related mortality. Patients who received STR and/or had atypical tumors (criteria = Ki-67 &amp;gt;4%) experienced decreased RFS compared to those who received GTR and/or were without atypical tumors. RFS at 5 years was 67% for typical CNs and 22% for atypical CNs. Every pediatric tumor was atypical and 3/5 recurred within 5 years. Salvage RT following tumor recurrence led to 100% tumor control, with no further recurrences (median post-RT follow-up = 5.79 years); volumetric analysis for 3 recurrent tumors (8.59 cumulative years of serial scans) revealed an ~80% reduction in tumor (range: 76.3%-81.1%), at a mean rate of 2.49% per month. CONCLUSION We provide encouraging evidence that (1) CNs have limited long-term risk of tumor-related mortality and (2) RT after tumor recurrence conveys strong long-term tumor control, including for potentially more aggressive pediatric CNs. Our institutional experience supports the conservative management of CN, including withholding RT until signs of recurrence regardless of resection extent or Ki-67.
IMMU-50. DIFFERENCES IN GUT MICROBIAL COMPOSITION BETWEEN PEDIATRIC BRAIN TUMOR PATIENTS AND HEALTHY CONTROLS – THE MIMIC PROGRAM
Authors: Raoull Hoogendijk, Thijs van den Broek, Tiago Carvalheiro, Julie Lammers, Monique Legemaat, Miguel Quaedvlieg, Esther van Mastrigt, Marcel de Zoete, Janetta Top, Sabine Mueller, Cassie Kline, Friso Calkoen, Jasper van der Lugt
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The gut microbiome has been hypothesized to influence tumor initiation, immune evasion and treatment response in CNS tumor patients via the gut-brain axis, but data remains limited. To begin to address this question, we compared the gut microbial composition in a cohort of pediatric high-grade brain tumor patients with healthy controls. METHODS Within the MIMIC program, we prospectively collected fecal samples from 33 pediatric brain tumor patients at diagnosis and 26 pediatric healthy controls (HC) (&amp;lt; 21 years of age). Samples were analyzed using 16S rRNA amplicon sequencing of the V3-V4 region. Group differences were tested through the α- and β-diversity. Additionally, differential abundance (DA) analyses were performed. RESULTS Brain tumor patients (16 embryonal and 17 glial) significantly differed in age from HC (median 8 years vs 5 years, p&amp;lt; 0.001). Patient vs HC comparison revealed a comparable α-diversity (Shannon-index p=0.45), but significantly different β-diversity (Permanova test p=0.02). Corrected for age, DA revealed 18 genera with a significant log fold change. Twenty five of 33 brain tumor patients received dexamethasone during or prior to fecal sampling and 32 out of 33 patients received cefazolin, a first generation narrow-spectrum cephalosporin targeting mainly gram-positive bacteria, during surgery and before sample collection. Steroid use within brain tumor patients did not statistically affect α-diversity, β-diversity or DA. However, the impact of intravenously administered cefazolin during surgery on the gut microbiome in brain tumor patients remains unknown. CONCLUSION We report significant differences in gut microbial composition between pediatric brain tumor patients at diagnosis and healthy controls. DA revealed clinically relevant differences in Agathobacter , Fusicatenibacter , Eggerthella , and Hungatella. However, differences may be impacted by cefazolin administration. If and how gut microbial composition at diagnosis is associated with treatment efficacy and toxicity is subject to further research within the MIMIC program.
NIMG-02. ADVERSE RADIATION EFFECT VERSUS TUMOR PROGRESSION FOLLOWING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: IMPLICATIONS OF RADIOGRAPHIC UNCERTAINTY
Authors: Mia Salans, Lisa Ni, Lauren Boreta, Philip Theodosopoulos, Olivier Morin, Steve Braunstein
Journal: Neuro-Oncology (2023)

Abstract Despite efforts from RANO to standardize treatment response reporting, adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases (BM) remains challenging to distinguish from tumor progression (TP) due to radiographic uncertainty (RU), often necessitating serial imaging until definitive diagnosis (DD) is resolved. We characterized management and implications of RU after BM irradiation for multiple primary tumor histologies. We identified 138 BM cases reviewed at our multi-disciplinary SRS Tumor Board (TB) for RU of ARE versus TP on MRI following SRS between 2015-2022. Target diameter (mm), histology, location, and SRS dose (Gy) on initial treatment and lesion diameter, associated symptoms, and supportive medications at the time of TB presentation were extracted from the medical record. Final lesion etiology, use of any intervention, and neurologic deficits upon DD were documented. Time from RU to DD was calculated. Median time from SRS to initial RU was 11.3 months (IQR 5.5-18.2). Median RU lesion diameter was 14.0 (IQR 8.0-20.0). At the time of RU, 43% of patients were symptomatic, 28% and 4% requiring steroids and bevacizumab, respectively. Time to DD following RU was &amp;gt; 6 and 12 months in 28% and 8% of patients, respectively (maximum 47 months). Median lesion diameter at DD was 16.0 mm (IQR 10.3-24.0). Most (54%) had a DD of ARE, while 41% had TP; 23% and 77% were diagnosed pathologically and radiographically, respectively. Upon DD, 41% underwent local intervention with surgery and/or re-irradiation and 25% had a new neurologic deficit, including weakness (7%), ataxia (5%), and aphasia (4%). In an interdisciplinary setting, it took &amp;gt; 6 months to reach a DD after RU in &amp;gt; 25% of patients previously irradiated for BM. Diagnostic uncertainty and delay may lead to sub-optimal outcomes and symptom burden. Improved characterization of post-SRS imaging findings is needed in this population.
BIOS-02. RECAPITULATE TUMOR DIVERSION AND SPATIAL PATTERNING IN GLIOBLASTOMA BACKGROUND
Authors: Wei-Lun Lo, Hoang Dang Ta Khoa, Jian-Ying Chuang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Intra-tumoral heterogeneity of glioblastoma multiforme (GBM) drives aggressive behavior and intrinsic therapeutic resistance. To investigate heterogeneity, high-resolution sequencing techniques provided us to feature tumor molecular subtyping and simulate differentiation. In our study, we proposed to dissect tumor heterogeneity in different anatomical regions by single cell transcriptome analysis. Material and Method We performed single-cell RNA sequencing on 10675 adult IDH-wild type GBM cells from six pairs of tumor core (central necrotic part of tumor) and tumor margin (junction between tumor and brain). Subtyping following RNA velocity was performed to investigate tumor diversity. Result Four subgroups of tumor cells (OPC-like (oligoprogenitor cell), NPC-like (neuroprogenitor cell), AC-like (astrocyte), and MES-like (mesenchymal) )were identified. The higher cell population of OPC/NPC at tumor margin and AC/MES at tumor core was found. The RNA velocity analysis showed the major diversity order was OPC at margin, OPC at core, NPC at margin, and AC with MES at core. CONCLUSION We explore the spatial pattern of tumorigenesis of GBM that OPC at margin part could be the tumor initiating cell. Further investigation of biological characteristics of OPC could be the strategies to block tumor differentiation and progression.